Nardilysin and OGDHL: Two Rare Genes That Add a Piece to the Brain Aging Puzzle

How can we understand brain aging that takes decades? Sometimes the best way is to learn from children who show it in an accelerated form. An international team from Texas Children's Hospital and Baylor College of Medicine, led by Prof. Hugo Bellen, followed two children with severe neurodegenerative symptoms that no one had been able to diagnose. They published in Neuron findings that not only solved the mystery but revealed a combination of mechanisms that help understand normal brain aging as well.

The Children: Two Cases, One Diagnosis

Two children, from different parts of the world, came for genetic testing with similar symptoms:

• Inability to walk
• Inability to eat independently
• Lack of speech
• Progressive reduction in brain size (acquired microcephaly)
• Gradual breakdown of motor and cognitive functions

Both functioned normally at birth, then began to decline. Standard genetic tests showed something strange: both children carried mutations in different genes. One in NRD1 (nardilysin), the other in OGDHL. No test had linked these two genes before.

The Connection: Both Damage the Same Metabolic Pathway

The Bellen team used a multi-pronged approach - examining what happens when the genes are removed from fruit flies, mice, and human cells in the lab. The findings coalesced into a single story:

1. NRD1 resides in the mitochondria. Its role is to assist in the proper folding of proteins. Specifically, it handles α-ketoglutarate dehydrogenase (OGDH), a key enzyme in the Krebs cycle.
2. OGDH/OGDHL are the same family. When nardilysin is absent, OGDH is not folded correctly, and cells cannot process α-ketoglutarate.
3. α-ketoglutarate accumulates in cells. Under normal conditions, it is converted for energy. When it accumulates, it activates mTORC1 - the cell's "growth switch."
4. mTORC1 activates protein synthesis and halts autophagy (cellular cleanup). This is disastrous for neurons, which thrive on autophagy to stay clean.
5. Neurons accumulate waste, lose function, and eventually die. Neurodegeneration.

"Two different genes, one pathway. If we understand the pathway, we have a way to treat."

The Solution: Rapamycin Reversed Symptoms

Rapamycin (Sirolimus) is a well-known drug that suppresses the mTORC1 pathway. It is commonly used in organ transplants as an immunosuppressant. The researchers asked: if the problem in the children is overactive mTORC1, would rapamycin help?

They tested this in fruit flies with the mutations. The result was dramatic:

• The untreated flies died young from loss of neural function
• The flies treated with rapamycin showed significant reversal of neurodegenerative symptoms
• Their lifespan approached that of healthy flies

This is not yet human medicine, but it is a proof of principle: genetic neurodegeneration via the NRD1/OGDHL pathway is reversible by suppressing mTORC1.

Why Is This Relevant to Everyone?

These children are very rare, but the pathway they reveal is not rare. In fact:

• Mitochondrial aging in each of us damages Krebs cycle enzymes, including OGDH
• α-ketoglutarate accumulates to some extent in every elderly person
• Overactive mTORC1 is a central feature of aging, linked to Alzheimer's and Parkinson's diseases
• Poor autophagy in older adults allows brain waste to accumulate

In other words: the extreme symptoms of the children show in an exaggerated form what happens to all of us. When we understand the mechanism in them, we understand it in everyone.

Rapamycin as a Longevity Drug?

This connection explains part of the great interest in rapamycin as a longevity drug. In mice, rapamycin is one of the few drugs that has consistently extended lifespan in controlled studies. The reason: it suppresses mTORC1, allows autophagy to work, and slows waste accumulation in all tissues, including the brain.

But rapamycin is not a drug without drawbacks:

• Suppresses the immune system. Risk of infections
• Impairs glucose and lipid metabolism
• Long-term effects are unclear

In human studies, the approach of low-dose, intermittent rapamycin (e.g., once a week instead of daily) shows benefits without many side effects. This is becoming a routine horizon in anti-aging.

What Can Be Done Without Medication?

Even without rapamycin, one can promote autophagy and lower mTORC1 through natural means:

• Intermittent fasting: 16/8 or 18/6 activates autophagy
• Physical activity: especially resistance training, balances mTORC1 (raises it temporarily, but lowers it overall)
• Mild caloric restriction: 10-15% reduction in calories lowers mTORC1
• Protein not in excess: a dose of 1.2-1.6 grams per kg is sufficient. Very high doses constantly activate mTORC1
• Green tea and coffee: contain compounds that lower mTORC1 (EGCG, chlorogenic acids)

Research Implications

The discovery by Bellen and his team opens the door to further studies. If NRD1 and OGDH/OGDHL are the focus, perhaps there is a way to develop drugs more specific than rapamycin that assist in this specific pathway. Studies are now underway on molecules that stabilize OGDH without affecting global mTORC1 pathways.

This is an example of what is good about medical research in the modern era: delving into rare diseases leads to insights about common diseases.